tbuckley/cabot-search huggingface dataset:
Abstract LB218: Developing a bispecific anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment
Authors: Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Jing Li, yaqiong zhou, Lei Nie, Gang Chen
Journal: Cancer Research (2023)

Abstract Developing a bispecific anti-ROR1 Antibody Drug Conjugate for hematological and solid tumor treatment Receptor tyrosine kinase ROR1 is a type I transmembrane protein belongs to the ROR family members. ROR1 is a receptor for Wnt family signaling molecules Wnt5a and is a key regulator of normal cellular process, including cell proliferation, survival, and migration. It is also involved in the development and progression of many types of cancer. Although being an oncofetal protein with limited expression in most of the normal tissues, ROR1 is expressed abnormally in various hematological and solid cancers, making it a highly attractive target for antibody-drug conjugate (ADC) therapy. The current clinical results of ROR1 ADC have been promising in treating patients with relapsed and/or refractory (R/R) hematologic malignancies. Utilizing our unique and innovated linker platform, we screened many anti-ROR1 ADCs, with defined DAR=4. Those unique ADCs consist of a humanized monoclonal antibody (mAb against single epitope) or a bispecific antibody (BsAb against two epitopes), stably conjugated to an antimitotic agent. The bispecific mAbs that target to two different epitopes of ROR1, are superior to those antibodies that target to single epitope in the binding to ROR1-expressing tumor cells, the induction of tumor cell death and anti-tumor immunity. Our novel linker structure prevents payloads from coming off of the antibody during the circulation, significantly reduced the off-target toxicity. In vitro and In vivo studies demonstrated the antitumor activity of anti-ROR1 ADCs outperformed the lead anti-ROR1 ADC currently in phase II/IIl trial, providing a promising treatment for hematological and solid cancers with a better safety profile and a larger therapeutic window. The lead candidate molecule, BR111A will start the preclinical studies soon. Citation Format: Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Jing Li, yaqiong zhou, Lei Nie, Gang Chen. Developing a bispecific anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB218.
Abstract LB098: Combination of a PD-1/CTLA-4 bispecific antibody with orally active PD-L1 inhibitor MAX-10181 effectively increased the percentage of tumors inhibited in animal model study
Authors: Yuguang Wang, Yuan Gao, Chenyu Mao, Nong Xu, Qiang Zhang, Jing Wang, Zhenhua Feng, Yonghong Zhu, Zhongmin Wang, Baiyong Li
Journal: Cancer Research (2023)

Abstract The key players in the current immuno checkpoint inhibition (ICI) treatment are antibodies or bispecific antibodies targeting PD-1. PD-L1 or CTLA-4. While these drugs provided a small number of patients with tumor shrinking (ORR between 10-30%) as a single agent, they did not lead to desirable treatment survival as measured by OS/PFS. Many combination studies are in progress in both preclinical and clinical settings to find an effective way to achieve prolonged OS/PFS in ICI treatment. Herein, we would like to report our most recent findings of combination of a PD-1/CTLA-4 bispecific antibody with our orally active, clinical stage PD-L1 inhibitor MAX-10181 in animal model study. The key observations are as follow: •The PD-1/CTLA-4 bispecific antibody group (n=10, average starting tumor volume= 68 mm3) demonstrated (a) 2 tumors (20%) in the slow volume shrinking mode with volume between 60-20 mm3, and (b) 4 tumors (40%) in the fast volume growing mode with volume above 500 mm3 •The combination group (n=10, average starting tumor volume= 68 mm3) demonstrated (a) 2 tumors (20%) in the fast volume shrinking mode with volume less than 20 mm3, (b) 1 tumor (10%) in the slow volume shrinking mode with volume between 60-20 mm3, and (c) only 1 tumor (10%) in the fast volume growing mode with volume above 500 mm3 These results indicate the potential of prolonged OS/PFS to combine PD-1/CTLA-4 bispecific antibody with orally active, small molecule MAX-10181 which recently completed Phase I trial. We will present the full study results in the coming AACR meeting. Citation Format: Yuguang Wang, Yuan Gao, Chenyu Mao, Nong Xu, Qiang Zhang, Jing Wang, Zhenhua Feng, Yonghong Zhu, Zhongmin Wang, Baiyong Li. Combination of a PD-1/CTLA-4 bispecific antibody with orally active PD-L1 inhibitor MAX-10181 effectively increased the percentage of tumors inhibited in animal model study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB098.
Abstract LB301: Molecular pharmacology and broad synergy of the novel ATR inhibitor M1774 with DNA damaging anticancer agents
Authors: Ukhyun Jo, Yasuhiro Arakawa, Astrid Zimmermann, Daiki Taniyama, Makito Mizunuma, Lisa M Jenkins, Suresh Kumar, Frank T Zenke, Yves Pommier
Journal: Cancer Research (2023)

Abstract Ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase orchestrates DNA damage response and repair pathways stimulated by replicative stresses. Recent studies have established that pharmacological inhibition of ATR is clinically promising. As M1774 is an oral ATR inhibitor in clinical development, we explored the molecular basis by which M1774 induces cancer cell death. As a single agent, we found that M1774 suppresses cancer cell viability at nanomolar concentrations with a potency higher than ceralasertib and berzosertib, but lower than gartisertib (M4344) and elimusertib in the small cell lung cancer (SCLC) cell lines H146, H82, and DMS114. We found that M1774 efficiently suppresses the ATR/CHK1 checkpoints. While M1774 alone induced apoptosis and G2/M cell cycle arrest at micromolar concentrations, at a non-toxic low dose, M1774 enhanced TOP1 inhibitor-mediated cancer cell death by preventing replication arrest and inducing DNA damage detected by EdU and γH2AX staining. Tandem mass tagging (TMT) coupled with mass spectrometry revealed that M1774 combined with SN-38 increases the expression of replication-related proteins (TIPIN, CDC45, TIMELESS, and RPA1) and G2/M-related proteins (PLK1 and CCNB1). To establish the synergistic combinations of M1774 with clinical anticancer DNA damaging agents in preclinical models, we performed experiments in cancer cell lines, patient-derived organoids, and xenograft models. Low doses of M1774 significantly synergized with the clinical TOP1 inhibitor SN-38, the TOP2 inhibitor etoposide, cisplatin, and the PARP inhibitor talazoparib in SCLC cell lines. We also found that M1774 significantly reversed chemoresistance to DNA-damaging agents in cancer cells lacking SLFN11 expression, suggesting that SLFN11 expression can be utilized for combination therapy with M1774 as a biomarker. The synergistic efficacy between M1774 and DNA-damaging agents was confirmed in SCLC patient-derived organoids, colon cancer patient-derived organoids, and H82 SCLC xenografts. Together, these results provide insights into the molecular mechanism and potential combination strategies for M1774 in cancer therapy. Citation Format: Ukhyun Jo, Yasuhiro Arakawa, Astrid Zimmermann, Daiki Taniyama, Makito Mizunuma, Lisa M Jenkins, Suresh Kumar, Frank T Zenke, Yves Pommier. Molecular pharmacology and broad synergy of the novel ATR inhibitor M1774 with DNA damaging anticancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB301.
Abstract LB267: Nitric oxide suppression by secreted frizzled-related protein 2 drives retinoblastoma
Authors: Panneerselvam Jayabal, Xiuye Ma, Kathryn M. Bondra, Yidong Chen, Peter J. Houghton, Yuzuru Shiio
Journal: Cancer Research (2023)

Abstract Retinoblastoma is a cancer of the infant retina primarily driven by the loss of the Rb tumor suppressor gene, which is undruggable. Here, we identified an autocrine signaling, mediated by secreted frizzled-related protein 2 (SFRP2), which suppresses nitric oxide and enables retinoblastoma growth. SFRP2 silencing resulted in rapid production of nitric oxide, leading to p53-dependent growth arrest of retinoblastoma cells. We show that coxsackievirus and adenovirus receptor (CXADR) is the cell surface receptor for SFRP2 in retinoblastoma cells, that CXADR functions as a "dependence receptor," transmitting a growth inhibitory signal in the absence of SFRP2, and that the balance between SFRP2 and CXADR determines nitric oxide production. Accordingly, high SFRP2 RNA expression correlates with high-risk histopathologic features in retinoblastoma. Targeting SFRP2 signaling by SFRP2-binding peptides or by a pharmacological inhibitor rapidly induced nitric oxide and profoundly inhibited retinoblastoma growth in orthotopic xenograft models. These results reveal a cytokine signaling pathway that regulates nitric oxide production and retinoblastoma cell proliferation, and is amenable to therapeutic intervention. Citation Format: Panneerselvam Jayabal, Xiuye Ma, Kathryn M. Bondra, Yidong Chen, Peter J. Houghton, Yuzuru Shiio. Nitric oxide suppression by secreted frizzled-related protein 2 drives retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB267.
Abstract LB121: BrainChild-03: Intraventricular B7-H3 CAR T cells for recurrent/refractory central nervous system tumors and non-pontine diffuse midline glioma in children and young adults
Authors: Nicholas A. Vitanza, Juliane Gust, Rebecca Ronsley, Ashley L. Wilson, Wenjun Huang, Kristy Seidel, Catherine M. Albert, Navin Pinto, Rimas J. Orentas, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park
Journal: Cancer Research (2023)

Abstract Background: B7-H3 expression on central nervous system (CNS) tumors offers a potential therapeutic target for adoptive cellular therapy. Methods: A 3+3 statistical design was employed to assess the safety of repeated B7-H3 chimeric antigen receptor (CAR) T cells administered into the intracranial ventricular system (ICV) using an intrapatient dose escalation without lymphodepleting chemotherapy in pts 1-26 years of age with recurrent/refractory CNS tumors including (non-pontine) diffuse midline glioma (DMG) (NCT04185038, Arm B). Primary endpoints were feasibility to manufacture sufficient CARs and safety of weekly infusions for 3 weeks of 4-week cycles for 2 cycles. Secondary endpoints were best overall response (BOR) and correlatives of CAR activity. Results: CAR manufacturing was achieved in 20/22 (91%) enrolled pts. Eight pts were inevaluable (rapidly progressive exam precluding initial infusion (n=5), removal from protocol therapy due to progressive disease (n=2), and lack of evaluable disease prior to initial infusion (n=1)). No dose limiting toxicities were observed, identifying the maximally tolerated dose regimen (MTDR) as DR3 (maximum dose: 10 × 107 B7-H3CARs). Subjects received 98 ICV doses (median: 6 doses/patient, range: 3-13). For evaluable patients, the most common adverse events were headache (12/12, 100%), fatigue (9/12, 75%), nausea/vomiting (7/12, 58%), and fever (6/12, 50%). There was no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Imaging analysis is ongoing with current BOR being stable disease. CAR T cells were detected in the CSF in 9/12 evaluable pts (75%). Serial CSF/serum cytokine analysis and mass spectrometry are in process. Conclusion: Repeated ICV administration of B7-H3 CAR T cells is tolerable with circulating CAR T cells detectable in the CSF post infusion. Further investigation is warranted, along with future studies interrogating iterative enhancements such as modifications for enhanced potency and multi-antigen targeting. Citation Format: Nicholas A. Vitanza, Juliane Gust, Rebecca Ronsley, Ashley L. Wilson, Wenjun Huang, Kristy Seidel, Catherine M. Albert, Navin Pinto, Rimas J. Orentas, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park. BrainChild-03: Intraventricular B7-H3 CAR T cells for recurrent/refractory central nervous system tumors and non-pontine diffuse midline glioma in children and young adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB121.
Abstract LB044: Modeling the role of ARID1A in colon cancer using patient-derived organoids
Authors: Luke T. Deary, Nicholas Sugiarto, Cameron Pigeon, Sara W. Mayo, Matthew Z. Wilson, Xiaofeng Wang
Journal: Cancer Research (2023)

Abstract Loss-of-function (LOF) mutations in genes encoding subunits of SWI/SNF chromatin remodeling complexes are found in approximately 25% of human cancers. Colorectal cancers (CRC), the second leading cause of cancer related deaths, are particularly vulnerable to SWI/SNF driver mutations, harboring subunit alterations in up to 55% of patient tumors. ARID1A, a BAF subcomplex specific subunit, is the most frequently mutated subunit in human cancers (12%) and CRCs (10-12%). Additionally, ARID1A was recently identified as a leading genetic alteration in inflammatory bowel diseases such as Crohn’s and Ulcerative Colitis, conditions which are at higher risk of developing CRC. These data suggest an important role in ARID1A regulation of colonic tissue homeostasis and the potential for ARID1A mutation as an initiating or early driving event in CRC, which has not yet been modeled in human colon tissues. To examine the role of ARID1A in colon cancer development, we took a bottom-up strategy using CRISPR edited patient-derived colon organoids to model ARID1A LOF mutations in combination with classic CRC mutations APC and TP53. We evaluated the functional consequences of ARID1A mutation on cell growth using colony formation and proliferation assays. To systematically investigate the phenotypic contribution of ARID1A loss in these cell contexts, we employed transcriptomic and epigenomic profiling with RNAseq and ATACseq. We found that triple knock-out (TKO) of ARID1A, APC and TP53 confers a growth advantage in colon organoids, and induces dramatic morphological changes such as loss of symmetry and the breakdown of cystic architectures. At the gene expression level, ARID1A mutations led to shared and cell context specific transcriptional changes enriched for pathways such as G2M checkpoint, KRAS Signaling, and STAT5 signaling. Mechanistically, we show that ARID1A dependent chromatin accessibility changes at putative enhancers are linked to promoters of differentially expressed genes. These data suggest that ARID1A can regulate multiple cancer hallmark pathways depending on the cellular context and indicate a pleiotropic tumor suppressive function requiring further investigation in clinically relevant genetic backgrounds. Citation Format: Luke T. Deary, Nicholas Sugiarto, Cameron Pigeon, Sara W. Mayo, Matthew Z. Wilson, Xiaofeng Wang. Modeling the role of ARID1A in colon cancer using patient-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB044.
Abstract LB178: Cell free RNA for prediction of PDAC in de novo symptomatic patients presenting for EUS-FNA
Authors: Travis Moore, Elias Spiliotopolous, Rowan Callahan, Ward Kirschbaum, Hyun Ji Kim, Dove Keith, Aaron Grossberg, Paul T. Spellman, Gordon Mills, Rosalie C. Sears, Terry Morgan, Thuy Ngo
Journal: Cancer Research (2023)

Abstract Endoscopic ultrasound (EUS), the primary procedure for the diagnosis of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer, is invasive. We aim to develop a liquid biopsy approach using plasma cell-free messenger RNA to stratify patients prior to EUS and assist in the precision diagnosis of PDAC. We found a set of plasma cell-free messenger RNA biomarkers and a set of robust reference genes to classify PDAC patients from intermediary pancreatic pathologies such as: benign cases, pancreatitis, and intraductal papillary mucinous neoplasm (IPMN) with reproducible results validated in separate cohorts. Our results demonstrate a non-invasive liquid biopsy approach for stratifying patient groups before invasive and definitive EUS screening. Citation Format: Travis Moore, Elias Spiliotopolous, Rowan Callahan, Ward Kirschbaum, Hyun Ji Kim, Dove Keith, Aaron Grossberg, Paul T. Spellman, Gordon Mills, Rosalie C. Sears, Terry Morgan, Thuy Ngo. Cell free RNA for prediction of PDAC in de novo symptomatic patients presenting for EUS-FNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB178.
Abstract LB337: Inhibition of the E3 ligase CBL-B enhances the effector function and proliferation of natural killer cells
Authors: Yilin Qi, Jun Kuai, Yingzhi Bi, David Greco, Samira Jaeger, Ken Carson, Hadi Danaee, Timothy Reilly, Geraldine Harriman, Fang Wang
Journal: Cancer Research (2023)

Abstract The E3 ubiquitin ligase CBL-B is a master regulator of effector T cells through its downstream regulation of T-cell receptor and co-stimulatory stimulation, but it has also been shown to play a negative feedback role in NK cells. CBL-B depletion enhances the production of IFNγ and the cytotoxicity of activated NK cells. Similar to the effect of depleting CD8 T cells in mice, depletion of NK cells abolishes the tumor growth delay observed in Cbl-b-/- mice. With emerging data supporting the potential role of exogenous NK cells in anti-tumor immunity, inhibition of CBL-B represents a promising approach to enhance both adaptive and innate immunity for cancer immunotherapy. Using one of our small molecules, allosteric CBL-B inhibitors, HOT-A, we demonstrated that CBL-B inhibition enhanced NK activation, IFNγ production and granzyme B secretion in response to the various stimulation conditions, including cytokines (such as IL-15 and IL12 + IL-18) and stimulatory receptors (such as NKp30 and NKG2D + CD244). NK cell proliferation was also enhanced in the presence of HOT-A. Single cell analysis further suggested that HOT-A increased NK polyfunctional cytokine expression during IL-12 + IL-18 activation. In a coculture system of NK cells and K562 target cells, HOT-A dose-dependently promoted primary human NK cell activation, cytokine production and cytotoxicity in the K562 cells. In the in vivo CT-26 tumor model, granzyme B+ NK cells in the TIL were significantly increased in the HOT-A treated tumor bearing mice and NK function gene signature was also increased by Nanostring analysis, suggesting an enhanced NK function in the tumor microenvironment. Taken together, the pre-clinical data presented here demonstrate that our CBL-B inhibitor enhances NK cell function in vitro and in vivo, suggesting that its enhancement of anti-tumor immunity may be driven through both effector T cell and NK cell-driven biology. Citation Format: Yilin Qi, Jun Kuai, Yingzhi Bi, David Greco, Samira Jaeger, Ken Carson, Hadi Danaee, Timothy Reilly, Geraldine Harriman, Fang Wang. Inhibition of the E3 ligase CBL-B enhances the effector function and proliferation of natural killer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB337.
Abstract LB151: Exploring the tumor microenvironment in a spatial context with SpaCET
Authors: Beibei Ru, Jinlin Huang, Yu Zhang, Kenneth Aldape, Peng Jiang
Journal: Cancer Research (2023)

Abstract Uncovering the composition and structure of the tumor microenvironment is critical to a mechanistic understanding of tumorigenesis and therapeutic resistance. Spatial transcriptomics (ST) technology has enabled profiling the molecular features of tumor tissue with position information. However, the spatial probe of various ST strategies with a 10~100 μm diameter might capture a mixture of transcripts from multiple cells or cell lineages. Cell type deconvolution in ST data of tumor tissues remains challenging for existing methods, which are designed to decompose general ST or bulk data. We develop the Spatial Cellular Estimator for Tumors (SpaCET) to infer cell identities from tumor ST data. Without the need of inputting cell references, SpaCET estimates malignant and non-malignant cell abundance by using a gene pattern dictionary of copy number alterations in common malignancies and a hierarchical atlas of immune/stromal cells, respectively. SpaCET provides higher accuracy than existing methods based on eight ST datasets on seven cancer types with matched double-blind histopathology annotations as ground truth. Furthermore, SpaCET can reveal the potential intercellular interactions at the tumor-immune interface by integrating inferred cell fractions with the ligand-receptor interaction network. We expect that SpaCET will be a valuable tool for spatial cancer biology. Citation Format: Beibei Ru, Jinlin Huang, Yu Zhang, Kenneth Aldape, Peng Jiang. Exploring the tumor microenvironment in a spatial context with SpaCET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB151.